[go: up one dir, main page]

US4599228A - Antimicrobial agent - Google Patents

Antimicrobial agent Download PDF

Info

Publication number
US4599228A
US4599228A US06/573,044 US57304484A US4599228A US 4599228 A US4599228 A US 4599228A US 57304484 A US57304484 A US 57304484A US 4599228 A US4599228 A US 4599228A
Authority
US
United States
Prior art keywords
sanguinarine
chloride
fluoride
glycerine
toxic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US06/573,044
Inventor
Peter A. Ladanyi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vipont Pharmaceutical Inc
Original Assignee
Vipont Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vipont Laboratories Inc filed Critical Vipont Laboratories Inc
Priority to US06/573,044 priority Critical patent/US4599228A/en
Application granted granted Critical
Publication of US4599228A publication Critical patent/US4599228A/en
Assigned to VIPONT PHARMACEUTICAL, INC. reassignment VIPONT PHARMACEUTICAL, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). 4-30-87 - DE Assignors: VIPONT LABORATORIES, INC., A CORP. OF DE (CHANGED TO)
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • This invention relates to the composition and preparation of an antimicrobial agent which may be used in dental preparations, surgical and other soaps, various other topical preparations, injectable medicines, and other drug applications.
  • the invention relates to compositions containing mineral acid salts of benzophenanthridine alkaloids mixed with a metal salt, preferably a metal salt of a mineral acid, although salts of mono- or dicarboxylic acids, among others, may also be used.
  • Sanguinaria canadensis Linne (Family: Papaveraceae) commonly known as blood root, red root, puccoon, etc.
  • the plant contains benzophenanthridine alkaloids including sanguinarine, chelerythrine, and several others.
  • the major alkaloids present are sanguinarine and chelerythrine.
  • the eighth edition of the Merck Index lists the alkaloids as sanguinarine, chelerythrine, protopine and homochelidonine.
  • the pure chemicals sanguinarine, chelerythrine, and other benzophenanthridine alkaloids can be isolated from other plants besides Sanguinaria. Also, they are available, even though very rarely, from some chemical supply houses.
  • the alkaloid sanguinarine in solution has been shown to have some antifungal and antiprotozoan properties.
  • the sanguinarine is applied as an emulsion topically to fungal infections.
  • the antibacterial activity of sanguinarine has been found to vary with the attached radicals, and various salts of sanguinarine have been shown to have some activity.
  • the hydrochloride and the sulfate salts have been found to have some activity against certain bacteria at various concentrations.
  • Sanguinarine nitrate is reported to have some weak bacteriostatic action on various types of bacteria.
  • the present invention relates to the preparation and the use of antimicrobial agents, formed particularly from mineral acid salts of benzophenanthridine alkaloids and a metal salt and useful in dental preparations, mouthwashes, rinses, surgical soaps, shampoos, creams, lotions, powders, injectables, etc., and other forms of drug preparation and disinfectants.
  • the mineral acid salts of the benzophenanthridine alkaloids may be used in various concentrations with a metal salt as an antimicrobial agent for use in treating both human and animal infections and diseases.
  • Metal salts particularly useful in the formulations of the present invention include metal salts of halogen acids.
  • these salts are zinc chloride, stannous fluoride, and sodium fluoride, although any metal salt can be used. This includes alkali, alkaline earth, and heavy metal fluorides, chlorides, bromides, and iodides.
  • non-toxic metal salts of halogen acids are preferred for use in the formulations according to the present invention, it has been found that non-toxic salts of other acids, such as mineral acids and mono-and dicarboxylic acids, are also effective.
  • acids, the non-toxic metal salts of which can be used include sulfuric acid, nitric acid, and acetic acid.
  • Glycerol is the preferred vehicle of the formulations according to the present invention, although other vehicles that can be used include organic solvents such as propylene glycol, dimethyl sulfoxide (DMSO), lower alcohols, and the like.
  • organic solvents such as propylene glycol, dimethyl sulfoxide (DMSO), lower alcohols, and the like.
  • Another object of the invention is to provide a benzophenanthridine alkaloid salt-metal salt preparation for treatment of periodontal disease, prevention of dental caries and similar oral cavity impairments.
  • Still another object of the invention is to provide drug preparation of a benzophenanthridine alkaloid and a metal salt, useful for treatment of ringworm infections, acne, cold sores and various parasitic infections.
  • Yet another object of the invention is to provide a drug preparation of a benzophenanthridine alkaloid and a metal salt, useful for treatment of scours in animals.
  • the drug preparation of the present invention can be incorporated in dental preparations, toothpastes, mouth rinses, surgical and other soaps, vehicles for topical applications, vehicles for parenteral or intramuscular injection, and the like.
  • the pure chemical either sanguinarine, chelerythrine, or other benzophenanthridine alkaloids, is dissolved in a chloroform/methanol mixture and acidified with a mineral acid such as hydrochloric acid.
  • a mineral acid such as hydrochloric acid.
  • the acidic mixture is evaporated to dryness and the residue is recrystallized from ethyl alcohol/chloroform, 50/50.
  • the mineral acid salt of the benzophenanthridine alkaloid is dissolved in either deionized water or C 1 -C 6 alcohols, glycerine, propylene glycol, petrolatum, or other organic solvents at 70 degrees C., and a metal salt or a salt-forming acid is added to the above solutions.
  • the preparations generally contain 0.1% by weight and up to 20% by weight of the benzophenanthridine alkaloid salt, and at least 1% and up to 60% by weight of a metal salt, with the remainder being the solvent.
  • the material can be diluted to the desired concentration, depending on the type of use, with the solvents listed above.
  • the benzophenanthridine alkaloid salt is used in preparations containing 0.01%-10% benzophenanthridine by weight.
  • the metal salt is present in amounts ranging from about 2% to about 60%. The lower concentrations are generally effective in the treatment of most diseases as explained below.
  • the basic preparation can be varied by using, in place of sanguinarine chloride, 0.3% of another mineral acid salt of a benzophenanthridine alkaloid, such as chelerythrine chloride.
  • a second example of a preparation is:
  • a third example of such a preparation is:
  • a fourth example of such a preparation for dental use is:
  • a 5-10% solution of the first basic preparation was used, applied directly to the infected area, one to three applications as indicated, 48 hours apart.
  • the etiological agent of this involvement is usually the mold known as Trychophyton album.
  • the duration of the disease is 4-12 months.
  • Sanguinarine chloride and chelerythrine chloride have strong antimicrobial properties.
  • Zinc chloride has antimicrobial properties only in high concentrations. It can be seen from Table I that sanguinarine chloride mixed with zinc chloride in a 1:1 ratio, as a rule, did not show a synergistic effect or even an additive action against most microorganisms tested in vitro. Further, it was found that in most cases the antimicrobial action of the sanguinarine chloride and zinc chloride mixture depended mostly on the amount of sanguinarine chloride present in the mixture, and was relatively independent from the amount of zinc chloride.
  • Zinc chloride in the concentrations required in vivo to have antimicrobial action caused blanching of tissue and, in some cases, chemical burns and other tissue damage. Further, zinc chloride was found to be slow acting in vivo as an antimicrobial agent.
  • Glycerine preparations containing sanguinarine chloride or other benzophenanthridine alkaloids and zinc chloride or stannous fluoride or sodium fluoride were fast acting, requiring only one to three applications to clear out infections rapidly. Further, these preparations did not appear to have the undesirable side effects of the zinc chloride in the concentration necessary to achieve antimicrobial effectiveness.
  • periodontal disease affects 2 out of 3 middle-aged Americans. Destruction of the tissue and structures that hold teeth fast in their sockets accounts for 75% of tooth loss after the age of 40. Most cases of periodontal disease are the result of neglect and can largely be prevented by a regular program of thorough hygiene. In the most common type of periodontal disease, the three chief culprits are bacteria, calculus (tartar), and food debris.
  • the invention has been used by dentists in clinical management of over forty cases of various types of human periodontal disease.
  • the clinical procedure consisted of two treatments approximately two weeks apart, with the application of not less than 1.0 mm thickness of the basic preparation to the diseased periodontium.
  • undiluted material was either applied topically with a spatula or 0.25 ml was pressed through a 22 gauge needle attached to a 1.0 ml pressure syringe.
  • the material was introduced into the gingivae to the attachment (q.s.) to fill the pocket and the medication was left in place for 10-15 minutes.
  • gingipak contains racemic epinephrine hydrochloride 8-100 solution and 1% benzyl aclohol as preservative.
  • Cotton strings 1-1.5 cm in length were saturated with undiluted material by using a spatula and precut pieces of string which were then impregnated on a dentist's mixing pad. These strings, when properly impregnated with the preparation, weigh approximately 35 mg/cm.
  • strings were used per tooth depending upon the circumference of the tooth. Up to three strings were sometimes used for a total of approximately 10.5 mg of the preparation. Inpregnated strings were left in place 10-15 minutes.
  • Dental floss or similar substrate such as synthetic hollow fiber string
  • the basic preparation for use in treating the teeth and gums.
  • irrigation was often used concurrently as part of regimen.
  • the diseased periodontium was first packed with undiluted preparation or the teeth were individually treated by the string technique described above. These methods of treatment were followed by irrigation with a suspension of the preparation in either water or glycerine.
  • Suspensions were prepared to contain 1 part of full strength material to 1 part of glycerine, or 1 part of water depending on whether a glycerine or water suspension was desired.
  • the final suspension was V/V mixture of 1 part material to 1 part diluent. Irrigation was accomplished by filling a 7.0 ml syringe to contain 420 mg of the suspension.
  • a total of 1.0 ml of material in suspension was used to irrigate the buccal, lingual, and interproximal areas about the tooth. Where indicated, all teeth were irrigated with 840 mg of the suspension contained in two syringes.
  • Preparations containing about 0.3% sanguinarine chloride and about 35% zinc chloride were used on seven patients with dental caries. Decay was removed from the teeth with a spoon excavator leaving a layer of carious tissue about 1 mm to 11/2 mm in depth. The antimicrobial preparation was placed over the remaining decay, about 56.1 mg of preparation, with a Hollenbeck carver and uniformly applied over the decayed area with a piece of cotton held in cotton tweezers. Intermediate restorative material (IRM) was used as a temporary restoration to seal the material in the cavity preparation.
  • IRM Intermediate restorative material
  • the preparation could be considered a cariostatic agent.
  • the material may enhance sclerotic dentine formation, thus forming a hard protective floor between the carious lesion and the pulp.
  • the benzophenanthrine chloride-zinc chloride-glycerine composition can be used in conjunction with a fluoride-providing compound.
  • fluoride-providing compound These compounds are characterized by the ability to release fluoride ions in water and by substantial freedom from reaction with other compounds present in the oral preparation.
  • inorganic fluoride salts such as suitable alkali metal, alkaline earth metal, and heavy metal salts.
  • the amount of the fluoride-providing compound is dependent to some extent upon the type of compounds, its solubility, and the type of oral preparation, but it must be a nontoxic amount. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release from 0.005% to 1%, most preferably about 0.1% by weight of fluoride ion. Typically, in the cases of alkali metal fluoride and stannous fluoride, this component is present in an amount up to 3% by weight, based on the weight of the preparation, and preferably in the range of from 0.05% to 1%.
  • a 150 ug/ml and a 20 ug/ml solution also inactivates the cultures of yeasts Candida albicans and Saccharomyces cerevisiae.
  • a considerably lower concentration than the inactivation concentration of the drug preparation is useful as a growth inhibitor of the same organisms.
  • compositions of the present inventicn to cold sores enormous hastens the healing process. Cold sores dry up and heal in a few days.
  • the recovery rate exceeds that of the antibiotics commonly used for the purposes of treating scours.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Birds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

An antimicrobial agent comprising a mineral acid salt of a benzophenanthridine alkaloid in a mixture with a metal salt of an acid.

Description

BACKGROUND OF THE INVENTION
This application is a continuation of application Ser. No. 226,088 filed Jan. 19, 1981, and now abandoned, which is a continuation-in-part of Ser. No. 151,706, filed May 20, 1980, and now abandoned, which is a continuation-in-part of Ser. No. 24,604, filed Mar. 28, 1979, and now abandoned.
This invention relates to the composition and preparation of an antimicrobial agent which may be used in dental preparations, surgical and other soaps, various other topical preparations, injectable medicines, and other drug applications. In particular, the invention relates to compositions containing mineral acid salts of benzophenanthridine alkaloids mixed with a metal salt, preferably a metal salt of a mineral acid, although salts of mono- or dicarboxylic acids, among others, may also be used.
One of the important sources of sanguinarine is a perennial herb native to North America called Sanguinaria canadensis Linne (Family: Papaveraceae) commonly known as blood root, red root, puccoon, etc. The plant contains benzophenanthridine alkaloids including sanguinarine, chelerythrine, and several others. The major alkaloids present are sanguinarine and chelerythrine. The eighth edition of the Merck Index lists the alkaloids as sanguinarine, chelerythrine, protopine and homochelidonine. The pure chemicals sanguinarine, chelerythrine, and other benzophenanthridine alkaloids can be isolated from other plants besides Sanguinaria. Also, they are available, even though very rarely, from some chemical supply houses. Semi-purified forms of the alkaloids are commercially available, and these are generally referred to as sanguinarine nitrate and sanguinarine sulfate. These "salts" are the salts of the mixed alkaloids of the plant Sanguinaria: mainly sanguinarine, chelerythrine, and protopine. While few references can be found in the literature regarding the usage of any of the pure benzophenanthridine alkaloids, plants containing such compounds have been used for medical purposes for quite some time for a wide variety of ailments.
The principle use of sanguinarine up to recently was a stimulant expectorant to cough syrups containing "sanguinarine nitrate".
The use of sanguinarine with thiophosphoric acid in various animal and human neoplasms is shown in French patents, No. 70-22029 and 2,152,972.
The alkaloid sanguinarine in solution has been shown to have some antifungal and antiprotozoan properties. The sanguinarine is applied as an emulsion topically to fungal infections. The antibacterial activity of sanguinarine has been found to vary with the attached radicals, and various salts of sanguinarine have been shown to have some activity. The hydrochloride and the sulfate salts have been found to have some activity against certain bacteria at various concentrations. Sanguinarine nitrate is reported to have some weak bacteriostatic action on various types of bacteria.
SUMMARY OF THE INVENTION
The present invention relates to the preparation and the use of antimicrobial agents, formed particularly from mineral acid salts of benzophenanthridine alkaloids and a metal salt and useful in dental preparations, mouthwashes, rinses, surgical soaps, shampoos, creams, lotions, powders, injectables, etc., and other forms of drug preparation and disinfectants. The mineral acid salts of the benzophenanthridine alkaloids may be used in various concentrations with a metal salt as an antimicrobial agent for use in treating both human and animal infections and diseases.
Metal salts particularly useful in the formulations of the present invention include metal salts of halogen acids. Among these salts are zinc chloride, stannous fluoride, and sodium fluoride, although any metal salt can be used. This includes alkali, alkaline earth, and heavy metal fluorides, chlorides, bromides, and iodides.
Although non-toxic metal salts of halogen acids are preferred for use in the formulations according to the present invention, it has been found that non-toxic salts of other acids, such as mineral acids and mono-and dicarboxylic acids, are also effective. Examples of acids, the non-toxic metal salts of which can be used, include sulfuric acid, nitric acid, and acetic acid.
Glycerol is the preferred vehicle of the formulations according to the present invention, although other vehicles that can be used include organic solvents such as propylene glycol, dimethyl sulfoxide (DMSO), lower alcohols, and the like.
It is therefore, among the object and advantages of the present invention to provide an antimicrobial agent of mineral acid salts of a benzophenanthridine alkaloid and a metal salt, useful for topical administration, injectables and other forms of drug preparations.
Another object of the invention is to provide a benzophenanthridine alkaloid salt-metal salt preparation for treatment of periodontal disease, prevention of dental caries and similar oral cavity impairments.
Still another object of the invention is to provide drug preparation of a benzophenanthridine alkaloid and a metal salt, useful for treatment of ringworm infections, acne, cold sores and various parasitic infections.
Yet another object of the invention is to provide a drug preparation of a benzophenanthridine alkaloid and a metal salt, useful for treatment of scours in animals.
These and other objects and advantages of the invention may be readily ascertained by the following description and examples of the preparation of the invention.
The drug preparation of the present invention can be incorporated in dental preparations, toothpastes, mouth rinses, surgical and other soaps, vehicles for topical applications, vehicles for parenteral or intramuscular injection, and the like.
PREPARATION OF ANTIMICROBIAL AGENT
The pure chemical, either sanguinarine, chelerythrine, or other benzophenanthridine alkaloids, is dissolved in a chloroform/methanol mixture and acidified with a mineral acid such as hydrochloric acid. The acidic mixture is evaporated to dryness and the residue is recrystallized from ethyl alcohol/chloroform, 50/50.
For use, the mineral acid salt of the benzophenanthridine alkaloid is dissolved in either deionized water or C1 -C6 alcohols, glycerine, propylene glycol, petrolatum, or other organic solvents at 70 degrees C., and a metal salt or a salt-forming acid is added to the above solutions. The preparations generally contain 0.1% by weight and up to 20% by weight of the benzophenanthridine alkaloid salt, and at least 1% and up to 60% by weight of a metal salt, with the remainder being the solvent. The material can be diluted to the desired concentration, depending on the type of use, with the solvents listed above.
The benzophenanthridine alkaloid salt is used in preparations containing 0.01%-10% benzophenanthridine by weight. The metal salt is present in amounts ranging from about 2% to about 60%. The lower concentrations are generally effective in the treatment of most diseases as explained below.
An example of a basic preparation:
______________________________________                                    
sanguinarine chloride                                                     
                  0.3%                                                    
glycerine U.S.P.  64.7%                                                   
zinc chloride AR  35.0%                                                   
______________________________________
The basic preparation can be varied by using, in place of sanguinarine chloride, 0.3% of another mineral acid salt of a benzophenanthridine alkaloid, such as chelerythrine chloride.
A second example of a preparation is:
______________________________________                                    
sanguinarine chloride                                                     
                  1.0%                                                    
glycerine U.S.P.  96.0                                                    
zinc chloride AR. 3.0%                                                    
______________________________________
A third example of such a preparation is:
______________________________________                                    
sanguinarine chloride                                                     
                  1.0%                                                    
glycerine U.S.P.  64.0%                                                   
zinc chloride AR. 35.0%                                                   
______________________________________
A fourth example of such a preparation for dental use is:
______________________________________                                    
sanguinarine chloride                                                     
                  1.0%                                                    
glycerine U.S.P.  95.6%                                                   
zinc chloride AR. 3.0%                                                    
stannous fluoride 0.4%                                                    
______________________________________
Additional formulations for a basic preparation are as follows:
______________________________________                                    
sanguinarine chloride                                                     
                  1.0%                                                    
stannous fluoride 0.4%                                                    
glycerine, U.S.P. 98.6%                                                   
______________________________________
and
______________________________________                                    
sanguinarine chloride                                                     
                  1.0%                                                    
sodium fluoride   3.0%                                                    
glycerine, U.S.P. 96.0%                                                   
______________________________________
Numerous types of diseases were treated in humans and in animals with the composition of the present invention as follows:
EXAMPLE 1 Canine Ringworm
A 5-10% solution of the first basic preparation was used, applied directly to the infected area, one to three applications as indicated, 48 hours apart.
EXAMPLE 2 Feline Ringworm
A 4-8% solution of the first basic preparations was applied directly to the infected area, 48 hours apart up to three applications.
EXAMPLE 3 Bovine Ringworm
The etiological agent of this involvement is usually the mold known as Trychophyton album. The duration of the disease is 4-12 months.
A 30% dilution of the first basic preparation is used, applied directly to the involved areas, 48 hours apart. Three applications proved to be adequate in treating the condition successfully.
EXAMPLE 4 Bovine Neo-natal Diarrhea
Twelve animals having diagnosed and confirmed neo-natal diarrhea were treated with 0.75 grams of the first basic preparation orally, once per animal, and showed clinical cure with one exception.
This constitutes an excellent result, considering that conventional antibiotic therapy currently in use has a much lower percentage of success.
Sanguinarine chloride and chelerythrine chloride have strong antimicrobial properties. Zinc chloride has antimicrobial properties only in high concentrations. It can be seen from Table I that sanguinarine chloride mixed with zinc chloride in a 1:1 ratio, as a rule, did not show a synergistic effect or even an additive action against most microorganisms tested in vitro. Further, it was found that in most cases the antimicrobial action of the sanguinarine chloride and zinc chloride mixture depended mostly on the amount of sanguinarine chloride present in the mixture, and was relatively independent from the amount of zinc chloride.
              TABLE I                                                     
______________________________________                                    
            Mean inactivating dose in micrograms                          
            per milliliter (μg/ml) of media.                           
                                 ZnCl.sub.2 & San-                        
                      Sanguinarine                                        
                                 guinarine                                
Microorganism ZnCl.sub.2                                                  
                      Chloride   Chloride (1:1)                           
______________________________________                                    
Bacillus subtilis                                                         
              25,000   22        1,000                                    
Escherichia coli                                                          
              6,250   270        500                                      
Klebsiella pneumoniae                                                     
              3,125   540        1,000                                    
Proteus vulgaris                                                          
              12,500  590        1,000                                    
Staphylococcus aureus                                                     
              6,250    70        500                                      
Streptococcus faecalis                                                    
              25,000  393        500                                      
Streptococcus mutans                                                      
              1,563   161         63                                      
Candida albicans                                                          
              --      150        --                                       
Saccharomyces cerevisiae                                                  
              6,250    20         63                                      
Pseudomonas aeruginosa                                                    
              3,500   7,000      400                                      
______________________________________
A separate test was conducted to determine the inhibitory concentration of sanguinarine chloride alone. These concentrations, for microorganisms in vitro, are as follows:
100 micrograms per milliliter for Escherichia coli
100 micrograms per milliliter for Candida albicans
50 micrograms per milliliter for Streptococcus mutans
10 micrograms per milliliter for Staphylococcus aureus
It was further found that a concentration of sanguinarine chloride of 25 micrograms per milliliter caused a 100% reduction of dental plaque by inactivating plaque forming microorganisms freshly collected from human dental plaque. Sanguinarine chloride compared favorably in vitro to chlorhexidine (Hibitane®), a material used as a standard in evaluating inhibition of human dental plaque forming microorganisms.
However, under in vivo test conditions, sanguinarine chloride was found to be ineffective against plaque forming microorganisms.
When sanguinarine chloride was applied to the affected area of both dogs and humans, repeated treatment with sanguinarine chloride alone did not reduce dental plaque or alleviate the symptoms of gingivitis or periodontal disease. Continuous treatment with sanguinarine chloride did not prevent the accumulation of dental plaque on teeth or prevent the occurrence of periodontal disease. However, it has been found that a combination of sanguinarine chloride and zinc chloride in glycerine is effective in vivo in reducing dental plaque and the incidence of periodontal disease, and has shown definite promise in the treatment and prevention of human periodontal disease.
Results of tests on guinea pigs with induced ringworm infection, dogs with periodontal disease, and humans with periodontal disease have shown that glycerine preparations of sanguinarine chloride plus zinc chloride are far superior for the management of infections in vivo than either zinc chloride or sanguinarine chloride alone.
When zinc chloride was replaced with a fluoride salt in the present preparations, the activity of the preparation against microorganisms believed to be associated with the causation of dental caries and periodontal disease (Streptococcus mutans), as well as other microorganisms, remained identical. Data supporting this phenomenon is presented in the following tables:
              TABLE II                                                    
______________________________________                                    
             Minimum Inhibitory Concentrations                            
             (MIC) in μg/ml                                            
               1.0% sanguinarine                                          
                            1.0% sanguinarine                             
               chloride 3.0%                                              
                            chloride 0.4%                                 
MICROORGANISM  zinc chloride                                              
                            stannous fluor-                               
TESTED         in glycerol  ide in glycerol                               
______________________________________                                    
Escherichia coli                                                          
                158          160                                          
Klebsiella pneumoniae                                                     
                158          160                                          
Proteus vulgaris                                                          
               --           --                                            
Streptococcus mutans                                                      
                79           80                                           
Streptococcus faecalis                                                    
               <20          <20                                           
Staphyloccoccus aureus                                                    
               <20          <20                                           
Pseudomonas aeruginosa                                                    
                630         1,280                                         
Saccharomyces cerevisiae                                                  
               <20          <20                                           
Candida albicans                                                          
                79          <20                                           
______________________________________                                    

              TABLE III                                                   
______________________________________                                    
             Minimum Inhibitory Concentrations                            
             (MIC) in μg/ml                                            
               1.0% sanguinarine                                          
                            1.0% sanguinarine                             
               chloride 3.0%                                              
                            chloride 0.4%                                 
MICROORGANISMS zinc chloride                                              
                            stannous fluor-                               
TESTED         in glycerol  ide in glycerol                               
______________________________________                                    
Bacteroides melaninogeni-                                                 
               8            8                                             
cus                                                                       
Eikenella corrodens                                                       
               32           32                                            
Actinomyces viscosus                                                      
               8            8                                             
Actinobacillus 16           16                                            
actinomycetemcomitans                                                     
Capnocytophaga gingivalis                                                 
               8            8                                             
Capnocytophaga sputigena                                                  
               8            8                                             
______________________________________                                    

              TABLE IV                                                    
______________________________________                                    
             Minimum Bactericidal Concentrations                          
             (MBC) in μg/ml                                            
               1.0% sanguinarine                                          
                            1.0% sanguinarine                             
               chloride 3.0%                                              
                            chloride 0.4%                                 
MICROORGANISMS zinc chloride                                              
                            stannous fluor-                               
TESTED         in glycerol  ide in glycerol                               
______________________________________                                    
Escherichia coli                                                          
               158          160                                           
Klebsiella pneumoniae                                                     
               1,261        640                                           
Proteus vulgaris                                                          
               2,522        640                                           
Streptococcus mutans                                                      
               158          160                                           
Streptococcus faecalis                                                    
               315          160                                           
Staphylococcus aureus                                                     
               158           80                                           
Pseudomonas aeruginosa                                                    
               2,522        2,560                                         
Saccharamyces cervisiae                                                   
                20           20                                           
Candida albicans                                                          
                79          160                                           
______________________________________
The above phenomenon is not what would be expected in light of the in vitro test results. In most cases sanguinarine chloride in vivo was only slightly effective or not at all. This was quite unexpected considering that in vitro all the antimicrobial activity of a sanguinarine chloride-metal salt mixture could be explained by the amount of sanguinarine present in the mixture.
Controlled clinical tests on 24 male beagle dogs showed that after four weeks of treatment the dogs treated with the zinc chloride-sanguinarine chloride-glycerine mixture had the lowest plaque and gingivitis scores, while the dogs treated with sanguinarine chloride alone had the highest. The dogs were treated topically once daily with the respective test formulation.
The results presented in Table V clearly indicate that the sanguinarine chloride-zinc chloride in glycerine treated group of dogs had lower gingivitis scores after four weeks of treatment than did the other groups. Zinc chloride alone was slightly active, but sanguinarine chloride alone showed no activity in vivo at all. This result is unexpected, considering that, in vitro, sanguinarine chloride is quite effective against microorganisms.
              TABLE V                                                     
______________________________________                                    
Oral Clinical Studies - Beagles (dogs)                                    
                              After                                       
Treatment            0 (start)                                            
                              4 weeks                                     
______________________________________                                    
                   Mean Gingivitis Scores                                 
None                 0.475    0.91                                        
0.1% Sanguinarine chloride                                                
                     0.495    0.942                                       
2.7% Zinc chloride   0.44     0.75                                        
0.1% Sanguinarine chloride with                                           
                     0.418    0.548                                       
2.7% zinc chloride in glycerine                                           
                   Mean Plaque Scores                                     
None                 7.478    12.408                                      
0.1% Sanguinarine chloride                                                
                     8.885    12.89                                       
2.7% Zinc chloride   8.76     10.15                                       
0.1% sanguinarine chloride with                                           
                     8.578    7.407                                       
2.7% zinc chloride in glycerine                                           
                   Mean Pocket Depths                                     
None                 1.459    1.458                                       
0.1% Sanguinarine chloride                                                
                     1.415    1.48                                        
2.7% Zinc chloride   1.46     1.37                                        
0.1% Sanguinarine chloride with                                           
                     1.445    1.44                                        
2.7% zinc chloride in glycerine                                           
______________________________________
Similar results occured, when the dogs were evaluated for the return of dental plaques (See Table V for plaque scores), sanguinarine chloride alone was not active in vivo. Zinc chloride was slightly preventive but the preparation of sanguinarine chloride-zinc chloride in glycerine not only prevented the return and further proliferation of dental plaque but significantly further reduced it during the four weeks of treatment.
Data also indicate that even the pocket depths were reduced somewhat by the treatment materials containing zinc chloride in glycerine, or zinc chloride-sanguinarine chloride in glycerine.
In a clinical test involving twenty volunteer patients with periodontal disease, it was observed that after treatment with benzophenanthridine alkaloid chloride-zinc chloride in glycerine, there was rapid improvement. Inflammation, infection and pockets were eliminated, abcesses ceased, gingival tone greatly improved, tissues healed, and in some cases normal tissue was restored and teeth mobility was reduced.
The clinical studies above showed that sanguinarine chloride in vivo was only slightly antimicrobial, very slow acting, or had no effect on the course of the infection at all.
Zinc chloride in the concentrations required in vivo to have antimicrobial action caused blanching of tissue and, in some cases, chemical burns and other tissue damage. Further, zinc chloride was found to be slow acting in vivo as an antimicrobial agent.
Glycerine preparations containing sanguinarine chloride or other benzophenanthridine alkaloids and zinc chloride or stannous fluoride or sodium fluoride were fast acting, requiring only one to three applications to clear out infections rapidly. Further, these preparations did not appear to have the undesirable side effects of the zinc chloride in the concentration necessary to achieve antimicrobial effectiveness.
EXAMPLE 5 Human Periodontal Disease
It has been reported that periodontal (gum) disease affects 2 out of 3 middle-aged Americans. Destruction of the tissue and structures that hold teeth fast in their sockets accounts for 75% of tooth loss after the age of 40. Most cases of periodontal disease are the result of neglect and can largely be prevented by a regular program of thorough hygiene. In the most common type of periodontal disease, the three chief culprits are bacteria, calculus (tartar), and food debris.
The invention has been used by dentists in clinical management of over forty cases of various types of human periodontal disease.
In some cases, even a single treatment brought major improvements in the conditions of the diseased gums. Clinical cure resulting from the treatment was quite apparent and included: elimination of inflammation, normal tissue tone restored, pockets were eliminated, infections were cleared up, mobility was reduced, and gingival tone was greatly improved.
The materials and methods used were the following:
1. Undiluted Paste for Packing:
In cases of widespread tissue involvement, undiluted preparation was used in quantity sufficient (q.s.) to "cover" or "pack" the infected or inflamed areas of gingival tissues.
The clinical procedure consisted of two treatments approximately two weeks apart, with the application of not less than 1.0 mm thickness of the basic preparation to the diseased periodontium. In cases where undiluted material was used, it was either applied topically with a spatula or 0.25 ml was pressed through a 22 gauge needle attached to a 1.0 ml pressure syringe. The material was introduced into the gingivae to the attachment (q.s.) to fill the pocket and the medication was left in place for 10-15 minutes.
2. String Technique: Cotton String Saturated with the Drug Preparation.
In cases where individual teeth were to be treated, an ordinary soft cotton string, sterilized before use, or "gingipak" was used (gingipak contains racemic epinephrine hydrochloride 8-100 solution and 1% benzyl aclohol as preservative).
Cotton strings 1-1.5 cm in length were saturated with undiluted material by using a spatula and precut pieces of string which were then impregnated on a dentist's mixing pad. These strings, when properly impregnated with the preparation, weigh approximately 35 mg/cm.
One to three strings were used per tooth depending upon the circumference of the tooth. Up to three strings were sometimes used for a total of approximately 10.5 mg of the preparation. Inpregnated strings were left in place 10-15 minutes.
Dental floss or similar substrate, such as synthetic hollow fiber string, can be impregnated with the basic preparation for use in treating the teeth and gums.
3. Dilution of Paste for Irrigation
In addition to "packing" of the periodontium or employing the "string technique" on individual teeth, irrigation was often used concurrently as part of regimen. Generally, the diseased periodontium was first packed with undiluted preparation or the teeth were individually treated by the string technique described above. These methods of treatment were followed by irrigation with a suspension of the preparation in either water or glycerine. Suspensions were prepared to contain 1 part of full strength material to 1 part of glycerine, or 1 part of water depending on whether a glycerine or water suspension was desired. The final suspension was V/V mixture of 1 part material to 1 part diluent. Irrigation was accomplished by filling a 7.0 ml syringe to contain 420 mg of the suspension. For treatment of individual teeth, a total of 1.0 ml of material in suspension was used to irrigate the buccal, lingual, and interproximal areas about the tooth. Where indicated, all teeth were irrigated with 840 mg of the suspension contained in two syringes.
EXAMPLE 6 Dental Caries
Preparations containing about 0.3% sanguinarine chloride and about 35% zinc chloride were used on seven patients with dental caries. Decay was removed from the teeth with a spoon excavator leaving a layer of carious tissue about 1 mm to 11/2 mm in depth. The antimicrobial preparation was placed over the remaining decay, about 56.1 mg of preparation, with a Hollenbeck carver and uniformly applied over the decayed area with a piece of cotton held in cotton tweezers. Intermediate restorative material (IRM) was used as a temporary restoration to seal the material in the cavity preparation.
After several weeks (6 weeks) specimens for bacterilogical and histological studies, including electron microscopy, were undertaken.
The conclusions of the investigators were that the preparation could be considered a cariostatic agent. Further, the material may enhance sclerotic dentine formation, thus forming a hard protective floor between the carious lesion and the pulp.
The benzophenanthrine chloride-zinc chloride-glycerine composition can be used in conjunction with a fluoride-providing compound. These compounds are characterized by the ability to release fluoride ions in water and by substantial freedom from reaction with other compounds present in the oral preparation. Among these materials are inorganic fluoride salts such as suitable alkali metal, alkaline earth metal, and heavy metal salts. Alkali metal and tin fluorides, such as sodium and stannous fluorides, and mixtures thereof, are preferred.
The amount of the fluoride-providing compound is dependent to some extent upon the type of compounds, its solubility, and the type of oral preparation, but it must be a nontoxic amount. Any suitable minimum amount of such compound may be used, but it is preferable to employ sufficient compound to release from 0.005% to 1%, most preferably about 0.1% by weight of fluoride ion. Typically, in the cases of alkali metal fluoride and stannous fluoride, this component is present in an amount up to 3% by weight, based on the weight of the preparation, and preferably in the range of from 0.05% to 1%.
EXAMPLE 13 Antimicrobial Activity
In order to illustrate the antimicrobial effectiveness of the composition according to the present invention, a series of in vitro and in vivo tests were performed. These tests were designed to demonstrate the lowest concentration of sanguinarine chloride that will inactivate microorganisms.
Findings were as follows:
On the average a 22 ug/ml sanguinarine chloride solution will inactivate cultures of the bacteria Bacillus subtilis, a 270 ug/ml solution cultures of Escherichia coli, a 540 ug/ml solution cultures of Klebsiella pneumoniae, a 590 ug/ml solution cultures of Proteus vulgaris, a 70 ug/ml solution cultures of Staphylococcus aureus, a 393 ug/ml solution cultures of Streptococcus faecalis, and a 161 ug/ml solution cultures of Streptococcus mutans (see Table I).
Further on the average a 150 ug/ml and a 20 ug/ml solution also inactivates the cultures of yeasts Candida albicans and Saccharomyces cerevisiae. A considerably lower concentration than the inactivation concentration of the drug preparation is useful as a growth inhibitor of the same organisms.
In addition, on the average a concentration of sanguinarine chloride presented in Table VI was sufficient per cubic centimeter of media, to inhibit growth of some fungi known to belong to the group of ringworm producing organisms.
              TABLE VI                                                    
______________________________________                                    
                Mean Inhibiting Dose of                                   
                Sanguinarine Chloride in ug/ml                            
Microorganisms  of Media                                                  
______________________________________                                    
Microsporum canis                                                         
                867                                                       
Microsporum nanum                                                         
                650                                                       
Trichophyton mentagrophytes                                               
                900                                                       
Trichophyton schoenleini                                                  
                467                                                       
Trichophyton terrestre                                                    
                467                                                       
Trichophyton vanbreuseghemi                                               
                750                                                       
______________________________________
The basic preparations were, on numerous occasions, also tested on a variety of animals and also humans infected with ringworm and athletes foot fungus. It was found that preparations according to the present invention will considerably hasten recovery from ringworm infection and facilitate rapid healing of lesions.
Results of clinical tests run by numerous dentists and dental institutions confirm that regular application of the composition of the instant invention to teeth surfaces will reduce the incidence of dental caries and the use on gums either by packing or irrigations will prevent or rapidly cure periodontal disease or microbial infections of the gums and surrounding tissues.
Application of the compositions of the present inventicn to cold sores immensely hastens the healing process. Cold sores dry up and heal in a few days.
When animals suffering from scours are treated internally with preparations according to the present invention, the recovery rate exceeds that of the antibiotics commonly used for the purposes of treating scours.

Claims (12)

What is claimed is:
1. A method for treating dental caries in humans comprising applying to the affected area an effective amount of a composition comprising from about 0.1% to 20% by weight of a non-toxic sanguinarine salt, from about 1% to about 60% by weight of zinc chloride, and from about 0.4% to about 3.0% by weight of a non-toxic fluoride salt, in a solvent selected from the group consisting of water, glycerine, propylene glycol, dimethyl sulfoxide, and C1-C6 alcohols.
2. The method of claim 1 wherein the solvent is glycerine.
3. The method of claim 1 wherein the non-toxic fluoride salt is selected from the group consisting of stannous fluoride and sodium fluoride.
4. The method of claim 3 wherein the non-toxic fluoride salt is stannous fluoride.
5. A method of treating gingivitis in humans comprising topically applying to the affected area an effective amount of a composition comprising from about 0.1% to about 20% by weight of a non-toxic sanguinarine salt, from about 1% to about 60% by weight of zinc chloride, and from about 0.4% to about 3.0% by weight of a non-toxic fluoride salt, in a solvent selected from the group consisting of water, glycerine, propylene glycol, dimethyl sulfoxide, and C1-C6 alcohols.
6. The method of claim 5 wherein the solvent is glycerine.
7. The method of claim 5 wherein the non-toxic fluoride salt is selected from the group consisting of stannous fluoride and sodium fluoride.
8. The method of claim 7 wherein the non-toxic fluoride salt is stanous fluoride.
9. A method of treating periodontal disease in humans comprising topically applying to the affected area an effective amount of a composition comprising from about 0.1% to about 20% by weight of a non-toxic sanguinarine salt, from about 1% to about 60% by weight of zinc chloride, and from about 0.4% to about 3.0% by weight of a non-toxic fluoride salt, in a solvent selected from the group consisting of water, glycerine, propylene glycol, dimethyl sulfoxide, and C1-C6 alcohols.
10. The method of claim 9 wherein the solvent is glycerine.
11. The method of claim 9 wherein the non-toxic fluoride salt is selected from the group consisting of stannous fluoride and sodium fluoride.
12. The method of claim 11 wherein the non-toxic fluoride salt is stannous fluoride.
US06/573,044 1981-01-19 1984-01-25 Antimicrobial agent Expired - Lifetime US4599228A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US06/573,044 US4599228A (en) 1981-01-19 1984-01-25 Antimicrobial agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22608881A 1981-01-19 1981-01-19
US06/573,044 US4599228A (en) 1981-01-19 1984-01-25 Antimicrobial agent

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US22608881A Continuation 1980-05-20 1981-01-19

Publications (1)

Publication Number Publication Date
US4599228A true US4599228A (en) 1986-07-08

Family

ID=26920200

Family Applications (1)

Application Number Title Priority Date Filing Date
US06/573,044 Expired - Lifetime US4599228A (en) 1981-01-19 1984-01-25 Antimicrobial agent

Country Status (1)

Country Link
US (1) US4599228A (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735945A (en) * 1986-03-13 1988-04-05 Vipont Laboratories, Inc. Method for inhibiting bone resorption and collagenase release
US5013553A (en) * 1987-06-30 1991-05-07 Vipont Pharmaceutical, Inc. Drug delivery devices
US5133981A (en) * 1989-11-17 1992-07-28 Atrix Laboratories, Inc. Purification of benzophenanthridine alkaloids extracts from alkaloid extracts
US5175000A (en) * 1987-06-30 1992-12-29 Vipont Pharmaceutical, Inc. Free amine benzophenanthridine alkaloid compositions
US5455024A (en) * 1993-05-19 1995-10-03 Church & Dwight Co., Inc. Dentifrices containing zinc oxide particles and sodium bicarbonate
GB2313543A (en) * 1996-05-29 1997-12-03 Procter & Gamble Compositions containing stannous halides and/or stannous carboxylates for the treatment of herpes virus infections
US5883153A (en) * 1993-04-15 1999-03-16 Shofu Inc. Fluoride ion sustained release preformed glass ionomer filler and dental compositions containing the same
US5939050A (en) * 1997-04-04 1999-08-17 Optiva Corp. Antimicrobial compositions
US6025365A (en) * 1997-03-25 2000-02-15 Arch Development Corp. Chelerythrine and radiation combined tumor therapy
WO2000048541A1 (en) * 1999-02-19 2000-08-24 Brooks Norman A Zinc chloride in treating skin diseases
US6248309B1 (en) 1997-04-04 2001-06-19 Optiva Corporation Gums containing antimicrobial agents
EP0920336A4 (en) * 1996-05-03 2002-02-13 Camas Technologies Inc Pesticides comprising benzophenanthridine alkaloids
WO2002002128A3 (en) * 2000-06-30 2002-04-25 Procter & Gamble Oral compositions comprising antimicrobial agents
US6579542B1 (en) * 2000-03-02 2003-06-17 Cecil Faulkner Treating feline-specific disorders by orally administering Hydrastis canadensis
US6596299B1 (en) * 2000-05-19 2003-07-22 Northern Research Laboratories, Inc. Method of treating periodontal disease
US20030206874A1 (en) * 1996-11-21 2003-11-06 The Proctor & Gamble Company Promoting whole body health
US6676953B2 (en) 2001-01-26 2004-01-13 Don L. Hexamer Antifungal composition and method for human nails
US6846478B1 (en) 1998-02-27 2005-01-25 The Procter & Gamble Company Promoting whole body health
US20050100563A1 (en) * 2001-01-26 2005-05-12 Hexamer Don L. Antifungal compositions and methods of treatment therewith
US20060193790A1 (en) * 2000-06-30 2006-08-31 The Procter & Gamble Company Promoting whole body health
WO2006116718A2 (en) 2005-04-28 2006-11-02 Proteus Biomedical, Inc. Pharma-informatics system
US20070053849A1 (en) * 2000-06-30 2007-03-08 The Procter & Gamble Company Oral care compositions containing combinations of anti-bacterial and host-response modulating agents
WO2008036682A2 (en) 2006-09-18 2008-03-27 Raptor Pharmaceutical Inc. Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates
EP2147679A2 (en) 2001-07-25 2010-01-27 Raptor Pharmaceutical Inc. Compositions and methods for modulating blood-brain barrier transport
WO2010095940A2 (en) 2009-02-20 2010-08-26 To-Bbb Holding B.V. Glutathione-based drug delivery system
WO2012044761A1 (en) 2010-09-29 2012-04-05 University Of North Carolina At Wilmington Ladder-frame polyether conjugates
EP4218718A2 (en) 2009-05-06 2023-08-02 Laboratory Skin Care, Inc. Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, 46:11332 j(1952). *
Chemical Abstracts, 52:7432 h(1958). *

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735945A (en) * 1986-03-13 1988-04-05 Vipont Laboratories, Inc. Method for inhibiting bone resorption and collagenase release
US5013553A (en) * 1987-06-30 1991-05-07 Vipont Pharmaceutical, Inc. Drug delivery devices
US5175000A (en) * 1987-06-30 1992-12-29 Vipont Pharmaceutical, Inc. Free amine benzophenanthridine alkaloid compositions
US5395615A (en) * 1987-06-30 1995-03-07 Vipont Pharmaceutical, Inc. Free amine benzophenanthridine alkaloid compositions
US5133981A (en) * 1989-11-17 1992-07-28 Atrix Laboratories, Inc. Purification of benzophenanthridine alkaloids extracts from alkaloid extracts
US5883153A (en) * 1993-04-15 1999-03-16 Shofu Inc. Fluoride ion sustained release preformed glass ionomer filler and dental compositions containing the same
US5455024A (en) * 1993-05-19 1995-10-03 Church & Dwight Co., Inc. Dentifrices containing zinc oxide particles and sodium bicarbonate
EP0920336A4 (en) * 1996-05-03 2002-02-13 Camas Technologies Inc Pesticides comprising benzophenanthridine alkaloids
GB2313543A (en) * 1996-05-29 1997-12-03 Procter & Gamble Compositions containing stannous halides and/or stannous carboxylates for the treatment of herpes virus infections
US20030206874A1 (en) * 1996-11-21 2003-11-06 The Proctor & Gamble Company Promoting whole body health
US6025365A (en) * 1997-03-25 2000-02-15 Arch Development Corp. Chelerythrine and radiation combined tumor therapy
US5939050A (en) * 1997-04-04 1999-08-17 Optiva Corp. Antimicrobial compositions
US6248309B1 (en) 1997-04-04 2001-06-19 Optiva Corporation Gums containing antimicrobial agents
US6846478B1 (en) 1998-02-27 2005-01-25 The Procter & Gamble Company Promoting whole body health
WO2000048541A1 (en) * 1999-02-19 2000-08-24 Brooks Norman A Zinc chloride in treating skin diseases
US6558694B2 (en) * 1999-02-19 2003-05-06 Norman A. Brooks Zinc chloride unit dose packaging, applicator, and method of use in treating cancer and other skin diseases
US6579542B1 (en) * 2000-03-02 2003-06-17 Cecil Faulkner Treating feline-specific disorders by orally administering Hydrastis canadensis
US6830757B2 (en) 2000-05-19 2004-12-14 Northern Research Laboratories, Inc. Method of treating periodontal disease
US6596299B1 (en) * 2000-05-19 2003-07-22 Northern Research Laboratories, Inc. Method of treating periodontal disease
US20070053849A1 (en) * 2000-06-30 2007-03-08 The Procter & Gamble Company Oral care compositions containing combinations of anti-bacterial and host-response modulating agents
US8277782B2 (en) 2000-06-30 2012-10-02 The Procter & Gamble Company Topical oral care compositions comprising host response modulating agents
US20050163727A1 (en) * 2000-06-30 2005-07-28 Doyle Matthew J. Promoting whole body health
US20060193790A1 (en) * 2000-06-30 2006-08-31 The Procter & Gamble Company Promoting whole body health
US8283135B2 (en) 2000-06-30 2012-10-09 The Procter & Gamble Company Oral care compositions containing combinations of anti-bacterial and host-response modulating agents
WO2002002128A3 (en) * 2000-06-30 2002-04-25 Procter & Gamble Oral compositions comprising antimicrobial agents
US6676953B2 (en) 2001-01-26 2004-01-13 Don L. Hexamer Antifungal composition and method for human nails
US20050100563A1 (en) * 2001-01-26 2005-05-12 Hexamer Don L. Antifungal compositions and methods of treatment therewith
US7048913B2 (en) 2001-01-26 2006-05-23 Hexamer Don L Antifungal composition and method for human nails
US20040057919A1 (en) * 2001-01-26 2004-03-25 Hexamer Don L. Antifungal composition and method for human nails
EP2147679A2 (en) 2001-07-25 2010-01-27 Raptor Pharmaceutical Inc. Compositions and methods for modulating blood-brain barrier transport
EP3827747A1 (en) 2005-04-28 2021-06-02 Otsuka Pharmaceutical Co., Ltd. Pharma-informatics system
EP2392258A1 (en) 2005-04-28 2011-12-07 Proteus Biomedical, Inc. Pharma-informatics system
WO2006116718A2 (en) 2005-04-28 2006-11-02 Proteus Biomedical, Inc. Pharma-informatics system
WO2008036682A2 (en) 2006-09-18 2008-03-27 Raptor Pharmaceutical Inc. Treatment of liver disorders by administration of receptor-associated protein (rap)-conjugates
WO2010095940A2 (en) 2009-02-20 2010-08-26 To-Bbb Holding B.V. Glutathione-based drug delivery system
EP4218718A2 (en) 2009-05-06 2023-08-02 Laboratory Skin Care, Inc. Dermal delivery compositions comprising active agent-calcium phosphate particle complexes and methods of using the same
WO2012044761A1 (en) 2010-09-29 2012-04-05 University Of North Carolina At Wilmington Ladder-frame polyether conjugates

Similar Documents

Publication Publication Date Title
US4406881A (en) Antimicrobial agent
US4599228A (en) Antimicrobial agent
CA1257547A (en) Oral composition
EP1272152B1 (en) Use of chlorhexidine in the prevention of root caries
CA2019410C (en) Liquid polymer composition, and method of use
US5438076A (en) Liquid polymer composition, and method of use
EP0577306B1 (en) Oral hygiene composition
CA1177407A (en) Antimicrobial agent
PL209943B1 (en) Use of quinolonyl- and quinolizine derivatives as chemical therapeutic agents
US8303938B2 (en) Anti-calculus dental composition
US4683133A (en) Method for treating periodontal disease
EP1115385B1 (en) Use of a composition for manufacturing a medicament for the prevention and treatment of parodontitis
US6440395B1 (en) Antiplaque mouth rinse
US8795638B1 (en) Compositions for dental care
Wilson et al. Effect of phenoxyethanol, chlorhexidine and their combination on subgingival plaque bacteria
CA1292695C (en) Anaerobe-selective antibacterial compositions and methods
BE888843A (en) PROCESS FOR PREPARING AN ANTIMICROBIAL AGENT, ANTIMICROBIAL COMPOSITION, MEDICAMENT COMPRISING THE SAME
KR20070102184A (en) Oral composition with excellent antimicrobial activity
CN108451792A (en) A kind of the polyethyleneimine mouthwash and its preparation method of anti-tartar calculus dentalis
KR20040019145A (en) Natural Mouthwash Formulation

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

RF Reissue application filed

Effective date: 19871117

FEPP Fee payment procedure

Free format text: PAT HOLDER CLAIMS SMALL ENTITY STATUS - SMALL BUSINESS (ORIGINAL EVENT CODE: SM02); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: VIPONT PHARMACEUTICAL, INC.

Free format text: CHANGE OF NAME;ASSIGNOR:VIPONT LABORATORIES, INC., A CORP. OF DE (CHANGED TO);REEL/FRAME:005270/0920

Effective date: 19870424

FEPP Fee payment procedure

Free format text: PAT HLDR NO LONGER CLAIMS SMALL ENT STAT AS SMALL BUSINESS (ORIGINAL EVENT CODE: LSM2); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

REMI Maintenance fee reminder mailed
FPAY Fee payment

Year of fee payment: 8

SULP Surcharge for late payment
REMI Maintenance fee reminder mailed
FPAY Fee payment

Year of fee payment: 12

SULP Surcharge for late payment